Spondias sp: Shedding Light on Its Vast Pharmaceutical Potential

Many plants are used by the population through popular knowledge passed from generation to generation for the treatment of various diseases. However, there is not always any scientific content supporting these uses, which is very important for safety. One of these plants is the fruit of the Spondias genus, which during its processing generates various residues that are discarded, but which also have pharmacological properties. The focus of this review is to survey the pharmacological activities that Spondias genus shows, as well as which part of the plant is used, since there is a lot of richness in its by-products, such as leaf, bark, resin, seed, and peel, which are discarded and could be reused. The main activities of this genus are antioxidant, anti-inflammatory, antidiabetic, antifungal, and antiviral, among others. These properties indicate that this genus could be used in the treatment of several diseases, but there are still not many products available on the market that use this genus as an active ingredient.


Introduction
There is considerable scientific interest toward the phytotherapy potential of medicinal plants which are viewed as extremely valuable for medical and pharmaceutical applications, due to their wide implementation in traditional medicine for centuries. These plants are believed to greatly contribute to the management of several diseases, being rich natural sources of new bioactive molecules and potential alternatives to available conventional medicinal products. One example of this is the genus Spondias.
Spondias L. is a genus of fruit trees that belongs to the Anacardiaceae family and comprises 18 species native to tropical South America, Asia, and Madagascar [1]. Considering all of the species, we can highlight the potential for exploitation and agro-industrial and pharmaceutical uses of S. mombin L. (known as yellow mombin or "cajá" in Brazil), S. dulcis or S. cytherea Parkinson (ambarella, golden apple, and cajarana or cajá-manga), S. purpurea L. (red mombin or siriguela), S. tuberosa Arruda Câmara (umbu or imbu), and S. pinnata [2].
The occurrence of species with intermediate characteristics among the already-described species of Spondias has been reported in several studies which have tried to determine the existence of hybrids in the genus [3]. Almost all evidence of Spondias hybridization includes S. mombin as one of the putative parents, and most of them occur where one or both putative parents occur or have been introduced [4]. In Brazil, cajá-umbu or umbu-cajá (S. mombin

Bioactive Compounds
Bioactive compounds, in general, are mainly secondary plant metabolites [22]. Among the bioactive compounds, polyphenols are considered the most abundant, and are generally related to defense against ultraviolet radiation or aggression by pathogens or insects [23]. Several classes of polyphenols are known, and their classification and differentiation were made according to the number of phenolic rings and the structural elements that bind their molecules. Flavonoids and non-flavonoids are considered to be the two main groups among polyphenols, some of which are specific to some plant species or genera [23].
In this context, one of the main characteristics of the Spondias species is the occurrence of flavonoids, as, in addition to performing different functions in plants (including defense, ultraviolet protection and flower color), these compounds also have important bioactive properties, such as antioxidant action, that are responsible for several benefits to human health [24]. In the study by Pereira, et al. [25] the correlation between the phenolic composition of five species of Spondias (Anacardiaceae) was described, namely, S. mombin, S. dulcis, S. purpurea, S. venulose, and Spondias sp. Through this study, the authors were able to understand the evolution of the phylogenetic relationships of these species. All samples analyzed showed similar phenolic compositions, with quercetin and rutin being the main bioactive compounds. Among the phenolic constituents found in the species of Spondias studied, except for S. dulcis, quercetin 3-O-rutinoside ( Figure 1) stood out. In addition, rutin ( Figure 1) was considered to be a compound shared by the studied species of American Spondias. Other studies have shown the presence of important bioactive compounds in Spondias sp. such as ellagic acid [6], gallic acid, catechin, chlorogenic acid, caffeic acid [26], and isoquercetin [27], though these are in lower concentrations.
Among the bioactive compounds, polyphenols are considered the most abundant, and are generally related to defense against ultraviolet radiation or aggression by pathogens or insects [23]. Several classes of polyphenols are known, and their classification and differentiation were made according to the number of phenolic rings and the structural elements that bind their molecules. Flavonoids and non-flavonoids are considered to be the two main groups among polyphenols, some of which are specific to some plant species or genera [23].
In this context, one of the main characteristics of the Spondias species is the occurrence of flavonoids, as, in addition to performing different functions in plants (including defense, ultraviolet protection and flower color), these compounds also have important bioactive properties, such as antioxidant action, that are responsible for several benefits to human health [24]. In the study by Pereira, et al. [25] the correlation between the phenolic composition of five species of Spondias (Anacardiaceae) was described, namely, S. mombin, S. dulcis, S. purpurea, S. venulose, and Spondias sp. Through this study, the authors were able to understand the evolution of the phylogenetic relationships of these species. All samples analyzed showed similar phenolic compositions, with quercetin and rutin being the main bioactive compounds. Among the phenolic constituents found in the species of Spondias studied, except for S. dulcis, quercetin 3-O-rutinoside ( Figure 1) stood out. In addition, rutin ( Figure 1) was considered to be a compound shared by the studied species of American Spondias. Other studies have shown the presence of important bioactive compounds in Spondias sp. such as ellagic acid [6], gallic acid, catechin, chlorogenic acid, caffeic acid [26], and isoquercetin [27], though these are in lower concentrations. Lima, et al. [28] carried out a study to determine the presence of secondary metabolites in the crude extract of the species Spondias sp. and S. tuberosa. The obtained data showed the presence of tannins, flavonoids, steroids, and terpenoids, though the presence of alkaloids and saponins was not found. These investigations indicated Lima, et al. [28] carried out a study to determine the presence of secondary metabolites in the crude extract of the species Spondias sp. and S. tuberosa. The obtained data showed the presence of tannins, flavonoids, steroids, and terpenoids, though the presence of alkaloids and saponins was not found. These investigations indicated promising results for the plant species studied, as the compounds found may be potentially active in biological and pharmacological applications [28].
As for antioxidant compounds, the cajá pulp showed significant amounts of phenolic compounds, in addition to high concentrations of carotenoids, tannins, and vitamin C. In this study, the authors identified five carotenoids, β-cryptoxanthin, lutein, zeinoxanthin, and αand β-carotene, with β-cryptoxanthin being mainly responsible for the high level of provitamin A activity in the pulp. More than 37% of the recommended daily allowance of vitamin A can be supplied with just one 100 g serving of cajá pulp [29].
Up to date, research on the Spondias species is scarce, and further investigation is required in order to substantiate the scientific knowledge of the bioactive compounds produced by these species, mainly in Brazilian biomes [28]. In fact, the Brazilian reality is such that although it has the greatest plant diversity in the world and many of its medicinal plants are widely known, the available information about these plants is still insufficient, especially given their potential applications, with specific emphasis on their biomedical applications [34].

Pharmacological Activity
S. mombin L. (Table 1) is a fruit tree distributed in the tropical areas of Africa, Asia, America, and in Brazil, mostly in the regions of the north and northeast [29]. The plant is known by several popular names such as cajá, cajá-mirim, and taperebá in Brazil and yellow mombin in North America [35]. The fruit has an exotic flavor and aroma, and plays an increasing role in agribusiness in the north and northeast regions of Brazil, being marketed mainly as a fresh fruit or processed pulp for use in juices, ice cream, popsicles, jellies, and yogurts [29].
S. mombin L. leaves are also used in traditional African medicine to treat neurological disorders. Studies have shown that it has sedative, anti-epileptic and antipsychotic, anxiolytic [41], and antidepressant [42] properties. These effects in the nervous system occur due to the presence of alkaloids and flavonoids in the leaves [43].
The results of this investigation show that S. mombin has several bioactive compounds that can contribute to pharmacological activity, which include antioxidant, antiinflammatory, antibacterial, molluscicidal, anti-epileptic, antipsychotic, anxiolytic, and antidepressant properties, and it has low toxicity, as can be seen in Table 1. It thus presents itself as a promising alternative to be applied in the pharmaceutical and cosmetic industries. Table 1. Summary of Spondias mombin L. activity in different parts of the plant, as described in the last few years.

Species
Activity Part of the Plant Evaluated References occur due to the presence of alkaloids and flavonoids in the leaves [43].
The results of this investigation show that S. mombin has several bioactive compounds that can contribute to pharmacological activity, which include antioxidant, anti-inflammatory, antibacterial, molluscicidal, anti-epileptic, antipsychotic, anxiolytic, and antidepressant properties, and it has low toxicity, as can be seen in Table 1. It thus presents itself as a promising alternative to be applied in the pharmaceutical and cosmetic industries.

S. dulcis or S. cytherea Parkinson
Leaves from Spondias dulcis ( Table 2) are used in folk medicine for skin infections and localized pain [47]. Crushed fruit is used to treat eye infections [48] and to treat itches, skin inflammation, sore throats, and ulcers [49]. Therefore, several studies aim to investigate the antimicrobial, immunomodulation, and antioxidant properties of different parts of S. dulcis. There are also studies which have explored the anticancer, thrombolytic, and enzyme inhibitory effects of S. dulcis.
Islam, Ahmed, Manik, Wahid and Kamal [49] performed antimicrobial screening of S. dulcis fruit and leaves via the disc diffusion method. Methanolic extracts of fruit and leaves were produced and then partitioned with dichloromethane and chloroform. All six S. dulcis extracts demonstrated moderate antimicrobial activity against Gram-positive and Gram-negative bacteria, such as P. aeruginosa, E. coli, S. aureus, Shigella boydii, and Salmonella paratyphi, and weak activity against Candida albicans. The same authors investigated the thrombolytic activity of S. dulcis extracts. All six extracts were significantly more thrombolytic than the negative control; however, the highest clot lysis induced by S. dulcis (25%) was lower than the positive control (50%).
S. dulcis presents other enzyme inhibitory effects, such as anti-α-glucosidase and antiα-amylase, responsible for the digestion of carbohydrates in the intestine. The inhibition of these enzymes is one of the mechanisms that reduces postprandial hyperglycemia in diabetic patients [50]. Ethanolic extracts from S. dulcis leaves [51] and fruit [52] presented anti-α-glucosidase activity with IC50 of 45.52 µg/mL and 4.73 µg/mL, respectively.
S. dulcis fruit aqueous extract presented anticancer activity against melanoma, a highly aggressive type of skin cancer [53]. The extract inhibited the in vitro proliferation, migration, and invasion of melanoma cells. In vivo, the tumor significantly reduced when

S. dulcis or S. cytherea Parkinson
Leaves from Spondias dulcis ( Table 2) are used in folk medicine for skin infections and localized pain [47]. Crushed fruit is used to treat eye infections [48] and to treat itches, skin inflammation, sore throats, and ulcers [49]. Therefore, several studies aim to investigate the antimicrobial, immunomodulation, and antioxidant properties of different parts of S. dulcis. There are also studies which have explored the anticancer, thrombolytic, and enzyme inhibitory effects of S. dulcis.
Islam, Ahmed, Manik, Wahid and Kamal [49] performed antimicrobial screening of S. dulcis fruit and leaves via the disc diffusion method. Methanolic extracts of fruit and leaves were produced and then partitioned with dichloromethane and chloroform. All six S. dulcis extracts demonstrated moderate antimicrobial activity against Gram-positive and Gram-negative bacteria, such as P. aeruginosa, E. coli, S. aureus, Shigella boydii, and Salmonella paratyphi, and weak activity against Candida albicans. The same authors investigated the thrombolytic activity of S. dulcis extracts. All six extracts were significantly more thrombolytic than the negative control; however, the highest clot lysis induced by S. dulcis (25%) was lower than the positive control (50%).
S. dulcis presents other enzyme inhibitory effects, such as anti-α-glucosidase and antiα-amylase, responsible for the digestion of carbohydrates in the intestine. The inhibition of these enzymes is one of the mechanisms that reduces postprandial hyperglycemia in diabetic patients [50]. Ethanolic extracts from S. dulcis leaves [51] and fruit [52] presented anti-α-glucosidase activity with IC 50 of 45.52 µg/mL and 4.73 µg/mL, respectively.
S. dulcis fruit aqueous extract presented anticancer activity against melanoma, a highly aggressive type of skin cancer [53]. The extract inhibited the in vitro proliferation, migration, and invasion of melanoma cells. In vivo, the tumor significantly reduced when treated with intraperitoneal injections of S. dulcis extract at 450 mg/kg for 15 days. S. dulcis reduced cyclooxygenase (COX-2) enzyme expression and downregulated CD133 glycoprotein, both associated with cancer growth, invasion, and metastasis. Further studies are required to identify the compounds responsible for the observed anticancer activity and to develop novel chemotherapeutic treatments for melanoma.
Ethanolic extracts of S. dulcis leaves and fruits presented IC 50 for DPPH scavenging assay of 14.22 µg/mL and 27.14 µg/mL, respectively [51,52]. Moreover, methanolic extracts were more effective antioxidants, with an IC 50 of 5.37 ug/mL for the leaves and IC 50 of 1.91 µg/mL for the fruit [49]. Methanol was also among the best solvents to extract phenolics from S. dulcis fruit (659.74 mg GAE/g) (gallic acid equivalent), leaves (609.71 mg GAE/g), and stem bark (657.31 mg GAE/g), and a positive correlation between antioxidant activity and total phenolic contents was observed [26].
In summary, S. dulcis extract and isolated fractions present relevant in vitro and in vivo pharmacological activity, with anticancer, antioxidant, antimicrobial, antimutagenic, antigenotoxic, thrombolytic, immunomodulation, and enzymatic inhibitory properties. Therefore, S. dulcis may be studied as a novel or synergistic approach to treat infections, skin disorders, and high-incident diseases, such as Alzheimer's, cancer, diabetes, and obesity. The authors have already demonstrated the promising practical applications of this plant in food technology and nanoscience for environment care. However, further studies are needed to apply the pharmacological potential that this species may offer. Table 2. Summary of Spondias dulcis activity in different parts of the plant, as described in the last few years.

Species
Activity Part of the Plant Evaluated References glycoprotein, both associated with cancer growth, invasion, and metastasis. Further studies are required to identify the compounds responsible for the observed anticancer activity and to develop novel chemotherapeutic treatments for melanoma. Ethanolic extracts of S. dulcis leaves and fruits presented IC50 for DPPH scavenging assay of 14.22 µg/mL and 27.14 µg/mL, respectively [51,52]. Moreover, methanolic extracts were more effective antioxidants, with an IC50 of 5.37 ug/mL for the leaves and IC50 of 1.91 µg/mL for the fruit [49]. Methanol was also among the best solvents to extract phenolics from S. dulcis fruit (659.74 mg GAE/g) (gallic acid equivalent), leaves (609.71 mg GAE/g), and stem bark (657.31 mg GAE/g), and a positive correlation between antioxidant activity and total phenolic contents was observed [26].
In summary, S. dulcis extract and isolated fractions present relevant in vitro and in vivo pharmacological activity, with anticancer, antioxidant, antimicrobial, antimutagenic, antigenotoxic, thrombolytic, immunomodulation, and enzymatic inhibitory properties. Therefore, S. dulcis may be studied as a novel or synergistic approach to treat infections, skin disorders, and high-incident diseases, such as Alzheimer's, cancer, diabetes, and obesity. The authors have already demonstrated the promising practical applications of this plant in food technology and nanoscience for environment care. However, further studies are needed to apply the pharmacological potential that this species may offer. S. purpurea L. (red mombin, Mexican plum, ciriguela) ( Table 3) [60] is a tropical medium-sized tree, whose fruit is an ellipsoid drupe which evidences a yellowish pulp and a thin yellow or reddish peel [61]. The fruit, which is consumed in both fresh and processed states, as juices, fermented beverages, wines, ice creams, and jams [60], constitutes a source of phenolic compounds, including tannins, phenolic acids, and flavonoids [61,62]. This plant represents a valuable source of income for many rural properties, due to its recognized sensorial and nutritional values, as well as the low cost of production [63]. In this context, the fruits and fractions of this species have been used 5.3. S. purpurea L.
S. purpurea L. (red mombin, Mexican plum, ciriguela) ( Table 3) [60] is a tropical medium-sized tree, whose fruit is an ellipsoid drupe which evidences a yellowish pulp and a thin yellow or reddish peel [61]. The fruit, which is consumed in both fresh and processed states, as juices, fermented beverages, wines, ice creams, and jams [60], constitutes a source of phenolic compounds, including tannins, phenolic acids, and flavonoids [61,62]. This plant represents a valuable source of income for many rural properties, due to its recognized sensorial and nutritional values, as well as the low cost of production [63]. In this context, the fruits and fractions of this species have been used in popular knowledge for centuries towards the management of a broad array of diseases, including diabetes, inflammatory reactions, diarrhea, and gastritis. These applications are largely due to its antioxidant, anti-inflammatory, and photoprotective activities [62], which have created interest in this species to be employed as promising ingredients of medical and cosmetic formulations.
Just as with the other genus Spondias species, S. purpurea L. evidences recognized antioxidant activity, which is mostly attributed to the presence of bioactive flavonoids and also to the phenolic content of the corresponding extracts [6,7,64]. Such evidence has been supported by several studies. Examples include the methanolic extract of S. purpurea L. crude peel [62], the hexane-based extract of the leaves of S. purpurea L. [65], and the hexane extract of the fruit of S. purpurea L. [66]. It must be highlighted that there are differences in the antioxidant properties and in the composition of functional active agents among all of the ecotypes [63,64].
In another context, the hexane and the ethanolic extracts of the leaves of S. purpurea showed the ability to reduce the area of ulcerative lesions in an in vivo ethanol-induced Molecules 2023, 28, 1862 7 of 16 gastric ulcer model. These results were compared with the nonsteroidal anti-inflammatory control drug (indomethacin), which revealed inferior percentages of protection. Thereby, hexane and the ethanolic extracts of the leaves of S. purpurea impacted on the minimization of ulcers, the enhancement of the levels of reduced glutathione, and the lowering of the tumor necrosis factor, clearly emphasizing the anti-ulcerogenic properties of this plant, indicating it as a potent anti-ulcer agent [65].
Curiously, recent studies have also been devoted to several other relevant applications of this species, looking at its inherent potential applications and greatly increasing the interest in this enriched natural source of bioactives. An example is the capacity of S. purpurea L. seed flour as a highly innovative ingredient that can substitute common refined (white) wheat flour in cakes due to its technological properties. What is more, the use of S. purpurea L. seed flour provides longer preservation of the product because of its antioxidant attributes, and also enhances the nutritional content of the food product [60].
Overall, studies with S. purpurea are scarce and constrained to fruits and gum exudates [65]. A variety of ecotypes that have not been characterized exist, and their adequate selection process, pertaining to their valuable functional properties, will enable the constitution of advanced protocols for this plant and fruit [63,64]. More studies should be performed to thoroughly investigate this plant and to thereby select or produce S. purpurea L. ecotypes with a higher content of antioxidant bioactives and more beneficial health properties [64], aiming for the significant implementation of the several inherent medical and cosmetic properties that this plant may offer. Table 3. Summary of Spondias purpurea L. activity in different parts of the plant, as described in the last few years.

Species
Activity Part of the Plant Evaluated References also to the phenolic content of the corresponding extracts [6,7,64]. Such evidence has been supported by several studies. Examples include the methanolic extract of S. purpurea L. crude peel [62], the hexane-based extract of the leaves of S. purpurea L. [65], and the hexane extract of the fruit of S. purpurea L [66]. It must be highlighted that there are differences in the antioxidant properties and in the composition of functional active agents among all of the ecotypes [63,64]. In another context, the hexane and the ethanolic extracts of the leaves of S. purpurea showed the ability to reduce the area of ulcerative lesions in an in vivo ethanol-induced gastric ulcer model. These results were compared with the nonsteroidal anti-inflammatory control drug (indomethacin), which revealed inferior percentages of protection. Thereby, hexane and the ethanolic extracts of the leaves of S. purpurea impacted on the minimization of ulcers, the enhancement of the levels of reduced glutathione, and the lowering of the tumor necrosis factor, clearly emphasizing the anti-ulcerogenic properties of this plant, indicating it as a potent anti-ulcer agent [65].
Curiously, recent studies have also been devoted to several other relevant applications of this species, looking at its inherent potential applications and greatly increasing the interest in this enriched natural source of bioactives. An example is the capacity of S. purpurea L. seed flour as a highly innovative ingredient that can substitute common refined (white) wheat flour in cakes due to its technological properties. What is more, the use of S. purpurea L. seed flour provides longer preservation of the product because of its antioxidant attributes, and also enhances the nutritional content of the food product [60].
Overall, studies with S. purpurea are scarce and constrained to fruits and gum exudates [65]. A variety of ecotypes that have not been characterized exist, and their adequate selection process, pertaining to their valuable functional properties, will enable the constitution of advanced protocols for this plant and fruit [63,64]. More studies should be performed to thoroughly investigate this plant and to thereby select or produce S. purpurea L. ecotypes with a higher content of antioxidant bioactives and more beneficial health properties [64], aiming for the significant implementation of the several inherent medical and cosmetic properties that this plant may offer. Table 3. Summary of Spondias purpurea L. activity in different parts of the plant, as described in the last few years.

Species Activity Part of the Plant Evaluated References
Spondias purpurea L.

S. tuberosa Arr. Câmara
S. tuberosa Arr. Câmara (umbu) ( Table 4) is an endemic fruit found in the caatinga, an exclusive Brazilian biome, characterized by semi-arid weather. The fruit belongs to the Anacardiaceae family, and it is characterized by its oval or ovoid shape. Furthermore, the pulp contains juice, with a sweet taste, which is full of antioxidant bioactives (phenolic compounds and carotenoids) and vitamin C [7,27,74,75]. Thus, there is interest in the manufactured by-products of this fruit; in fact, frozen pulps, nectar, and liqueurs are the most produced products in this industry [76].
Besides the manufacturing interest, its antioxidant activity has been targeted pharmacologically for cosmetic and medical use. Antioxidant compounds in the Spondias species are particularly relevant for the prevention and improvement of diseases related to oxidative stress. In the case of S. tuberosa, the presence of tannins and phenols in its peel has been reported [77,78], as well as organic acids in the peel, seeds, and pulp [78]. As well as this, total phenolic content in umbu was found to be high in the seed, peel, and pulp, consecutively.
In addition, umbu methanolic extract also demonstrated higher antioxidant activity when compared to ethanol and acetone extracts in studies where the three different extracts revealed antioxidant efficacy [79]. Additional studies evidenced lower phenolic compound detection using the liquid extract, suggesting that the components present in umbu are polar. In this study, the antioxidant activity of the liquid extract was not reduced, and, as a matter of fact, it was curiously higher [8]. Overall, the previous studies confirm the possible existence of polar bioactives that may increase the antioxidant capacity, but which may not necessarily be phenolic compounds.
In vivo studies conducted with diabetic rats treated with hydroalcoholic extract of umbu demonstrated an enzymatic antioxidant defense, which led to the conclusion that the plant may act as a radical capable of reducing oxidative stress in diabetic rats, protecting their functions, especially of the liver, from hepatic tissue damage [80].
In summary, many studies have proven the antioxidant capacity of S. tuberosa through DPPH, ABTS, ORAC, ascorbic acid, beta-carotene bleaching assay, and other tests [69,81,82]. According to these data, it is possible to confirm that the antioxidant activity from S. tuberosa is related to the phenolic content, even though this is lower than other fruits and plants. Moreover, the fruit part used in the studies may present different results of antioxidant activity intensity, in the same way that the form of liquid extract interferes in this activity. Such a result is attributed to the distribution of the phenolic content throughout different parts of the plant.
Umbu ethanolic seed extract presents inhibitory activity in acetylcholinesterase (AChE) [77]. This activity supports the use of umbu for degenerative conditions, such as Alzheimer's, given the antioxidant properties associated with AChE inhibition, which promote protection against free radicals [83].
The hexane extract of umbu leaves demonstrated the capability of inhibiting the growth of C. albicans and C. glabrata, contrary to C. parapsilosis and C. krusei, in which no fungicidal activity was detected. The extract was able to cause mitochondrial alteration and lysosomal compromise in C. glabrata functions. In this case, the hexane influenced bioactive absorption by the selection of a specific hyperoxide, 3-9-galactoside of quercetin, even though some antioxidant compounds must have been extracted due to the antioxidant capacity tests which characterized the solution as an antioxidant medium. Even considering these effects, the extract was classified by the authors as non-hemolytic [9].
According to in vitro tests in agar, S. tuberosa extract promoted a significant diffusion with Gram-negative bacteria, such as Klebsiella pneumonia, Serratia marcescens, Pseudomonas aeruginosa, Proteus mirabilis, Morganella morganii, Serratia liquefaciens, and Enterobacter cloacae. In comparison to ciprofloxacin, the minimum inhibitory concentration was (MIC 7.8 UG/ML) and a marked difference in antibacterial activity was found for the extract, which showed higher MIC values [37].
Bioactives in S. tuberosa branch extract, as mentioned before, contain significant antioxidant activity, demonstrating gastroprotective effects. In an in vitro gastric ulcer model, the use of branch extract of S. tuberosa improved the lesion when compared to the control group (lansoprazole). This is attributed to the ability of the antioxidant to capture the free radicals, and reduce the lesion in the gastric mucosa [84].
Due to the aforementioned discussion, S. tuberosa presented a promising source of bioactive compounds, endowed with relevant antioxidant, antidiabetic, anti-acetylcholinesterase, antibacterial, antifungal, gastroprotective, and non-cytotoxic documented properties. With this in mind, the umbu fruit presented a promising alternative for conventional therapies. Bioactives in S. tuberosa branch extract, as mentioned before, contain significant antioxidant activity, demonstrating gastroprotective effects. In an in vitro gastric ulcer model, the use of branch extract of S. tuberosa improved the lesion when compared to the control group (lansoprazole). This is attributed to the ability of the antioxidant to capture the free radicals, and reduce the lesion in the gastric mucosa [84].
Due to the aforementioned discussion, S. tuberosa presented a promising source of bioactive compounds, endowed with relevant antioxidant, antidiabetic, anti-acetylcholinesterase, antibacterial, antifungal, gastroprotective, and non-cytotoxic documented properties. With this in mind, the umbu fruit presented a promising alternative for conventional therapies. Table 4. Summary of Spondias tuberosa activity in different parts of the plant, as described in the last few years.

Spondias tuberosa
Antidiabetic Pulp [85] Peel, pulp, and seeds [12] Antioxidant Pulp [72,78,85] Peel, pulp, and seeds [12] 5.5. S. pinnata S. pinnata are decidua trees, also known as "kedondong hutan", and can reach 10 to 25 m with full growth. These trees are commonly found in primary and secondary forests [1,2,86]. They are characterized by a smooth bark, with irregular cracks and a gray to reddish-brown color, and the sap is transparent and viscous. Table 5 evidences some significant works related to the diverse kind of approaches using this promising plant, ranging from the most commonly used part in research-the bark-to other parts of the tree that have also been explored, such as resin, leaves, and fruit, among others. S. pinnata is distinguished from the other members of the genus, mainly by its short and pedicellate flowers, and by its endocarp characterized by a dense, fibrous, and hard outer layer. The roots, leaves, and fruit, among other parts of this tree, show numerous beneficial activities

Antidiabetic
Pulp [85] Peel, pulp, and seeds [12] Antioxidant Pulp [72,78,85] Peel, pulp, and seeds [12] 5.5. S. pinnata S. pinnata are decidua trees, also known as "kedondong hutan", and can reach 10 to 25 m with full growth. These trees are commonly found in primary and secondary forests [1,2,86]. They are characterized by a smooth bark, with irregular cracks and a gray to reddish-brown color, and the sap is transparent and viscous. Table 5 evidences some significant works related to the diverse kind of approaches using this promising plant, ranging from the most commonly used part in research-the bark-to other parts of the tree that have also been explored, such as resin, leaves, and fruit, among others. S. pinnata is distinguished from the other members of the genus, mainly by its short and pedicellate flowers, and by its endocarp characterized by a dense, fibrous, and hard outer layer. The roots, leaves, and fruit, among other parts of this tree, show numerous beneficial activities and therefore have been widely used in medicine and pharmacy in many countries [86]. The main pharmacological activities found include antioxidant, antimicrobial, anticancer, hypoglycemic, and anti-inflammatory activities, and are discussed below.
Hazra, et al. [87] evaluated the in vitro antioxidant properties of stem bark extract from S. pinnata. The antioxidant activities were evaluated for the scavenging of superoxide anions, hydroxyl radicals, hydrogen peroxide, nitric oxide, peroxynitrite, hypochlorous acid, and singlet oxygen, as well as for iron chelating capacity. The evaluated IC 50 values are 13.46, 112.18, 44.74, 24.48, 716.32, 127.99, and 58.07 µg/mL, respectively. These data are relevant as some illnesses are related to oxidative stress produced by free radicals. Thus, if the free radicals can be scavenged by antioxidants, many illnesses and ailments in living systems can be avoided, such as ageing, cardiovascular and inflammatory diseases, atherosclerosis, and cancer, among others.
In another work, Jain [2] verified the antioxidant and antibacterial properties of extracts from S. pinnata leaves, by using ethyl acetate and ethanol extracts which exhibited high scavenging activities. The highest flavonoid amount was obtained by ethyl acetate extract, while ethanol extract presented the highest total phenolic amount: 86.53 mg of quercetin equivalent (QE)/g extract and 27.76 mg GAE/g extract, respectively. Regarding the antibacterial activity, all of the extracts evaluated exhibited a variation from 8.33 to 28.67 mm of the inhibition zone. The ethanol extract tested against Staphylococcus aureus showed the lowest minimum bactericidal concentration (MBC) and MIC values of 3.5 and 2.0 mg/mL, respectively. Thereby, all of the extracts of S. pinnata leaf evaluated can be considered to have relevant formulations with antibacterial and antioxidant properties for pharmaceutical and medical applications.
The anti-inflammatory, antimicrobial, and cytotoxic effects of the fruit peel essential oil from S. pinnata were studied by Li, et al. [88]. These bioactivities demonstrated antiinflammatory activity by preventing nitric oxide production by endotoxin-introduced RAW 264.7 cells at concentrations of 0.08%, without any effect on cell viability. These bioactivities have also shown relative antibacterial activity against five pathogenic strains, (being Staphylococcus aureus, Acinetobacter baumannii, Pseudomonas aeruginosa, Aspergillus fumigatus, and Candida albicans), with a minimal fungicidal concentration (MFC) and MIC of 32 and 16 µg/mL, respectively. These values were 32-fold higher than the inhibition effect attained with Aspergillus fumigatus and tigecycline (a positive control), with a MBC and MIC of 1024 and 512 µg/mL, respectively. In addition, there was cytotoxic activity against five tumor cell lines (i.e., HL-60, SMMC-7721, A-549, MCF-7, and SW480 cell lines).
S. pinnata is also attracting growing attention regarding its application as a therapeutic anticancer source. Ghate, et al. [89] investigated the activity of bark extracts derived from this plant in inducing apoptosis in human breast adenocarcinoma and human lung adenocarcinoma cell lines (MCF-7 and A549, respectively). Results evidenced the anticancer potential of S. pinnata against cancer cells by inducing apoptosis through the modulation of Bcl-2 family proteins. Specifically, this extract exhibited cytotoxicity to both MCF-7 and A549 and cell lines (IC 50 of 149.34 and 147.84 µg/mL, respectively), while, for normal cells (i.e., human lung fibroblast WI-38 cells), no cytotoxicity was observed (IC 50 of 932.38 µg/mL).
With the aforementioned discussion in mind, S. pinnata constitutes a promising source of bioactive compounds, endowed with relevant and documented antioxidant, thrombolytic, antimicrobial, antidiabetic, and anticancer properties, being, thereby, presented as a promising alternative for conventional therapies. Table 5. Summary of Spondias pinnata activity in different parts of the plant, as described in the last few years.

Species Activity Part of the Plant Evaluated References
S. pinnata is also attracting growing attention regarding its application as a therapeutic anticancer source. Ghate, et al. [89] investigated the activity of bark extracts derived from this plant in inducing apoptosis in human breast adenocarcinoma and human lung adenocarcinoma cell lines (MCF-7 and A549, respectively). Results evidenced the anticancer potential of S. pinnata against cancer cells by inducing apoptosis through the modulation of Bcl-2 family proteins. Specifically, this extract exhibited cytotoxicity to both MCF-7 and A549 and cell lines (IC50 of 149.34 and 147.84 µg/mL, respectively), while, for normal cells (i.e., human lung fibroblast WI-38 cells), no cytotoxicity was observed (IC50 of 932.38 µg/mL).
With the aforementioned discussion in mind, S. pinnata constitutes a promising source of bioactive compounds, endowed with relevant and documented antioxidant, thrombolytic, antimicrobial, antidiabetic, and anticancer properties, being, thereby, presented as a promising alternative for conventional therapies.  (Table 6) is a fruit from the northeast of Brazil and is the result of the natural crossing between the species of S. mombin (cajá) and S. tuberosa (umbu). In the same way as umbu, the cajá-umbu fruit belongs to the Anacardiaceae family and is characterized by its oval shape, thin peel, and yellow color. Furthermore, the fruit has a sweet taste, which attracts the food industry for fruit extraction and the production of juices, candies, and ice cream [27]. Hepatoprotective Bark [91] 5.6. S. mombin × S. tuberosa S. mombin × S. tuberosa (cajá-umbu) ( Table 6) is a fruit from the northeast of Brazil and is the result of the natural crossing between the species of S. mombin (cajá) and S. tuberosa (umbu). In the same way as umbu, the cajá-umbu fruit belongs to the Anacardiaceae family and is characterized by its oval shape, thin peel, and yellow color. Furthermore, the fruit has a sweet taste, which attracts the food industry for fruit extraction and the production of juices, candies, and ice cream [27].
Besides its attractive taste, cajá-umbu contains important bioactives such as vitamin C, an important antioxidant, and other carbohydrates [27]. In fact, antioxidant activity was the prevalent activity studied in the literature for cajá-umbu. Phenolic compounds were found in the pulps of cajá-umbu at a total concentration of 62.08 ± 0.069. According to the DPPH test, cajá-umbu showed higher antioxidant activity when compared to the commercial antioxidant butylhydroxytoluene [78]. Accordingly, other authors obtained a DPPH result of 10.53 ± 0.19 mmol Trolox/g sample and FRAP of 0.31 d 0.01 mmol Trolox eq/g sample. These results were considered to be statistically significant, confirming the antioxidant activity [12].
More recently, the ORAC test (oxygen radical absorbance capacity) proved that residues of cajá-umbu, in an aqueous extract, were highly effective in their oxygen radical absorbance capacity. However, after oral consumption and gastrointestinal digestion, the antioxidant activity was reduced due to phenolic compound destabilization in intestinal pH. Even with the possible destabilization of the molecule by intestinal pH, the antioxidant capacity may not completely disappear, since the fermentation in the intestinal environment by bacteria may bio-convert the phenolic compounds [85].
Furthermore, cajá-umbu also demonstrated moderate to low inhibition of alphaglucosidase, as with many other fruits such as cashew apple, canafistula, cupuassu, soursop, manguba, strawberry [85], acerola, and pitanga [12], due to the flavonoids and phenolic compounds present. Interestingly, the concentration of flavonoids in cajá-umbu, which presents an important role in alpha-glucosidase inhibition, is present in lower values compared to the other fruits. In fact, only quercetin was significantly detected (3.38 ± 0.01 mg aglycone/100 g), and it showed no correlation with the activity of alpha-amylase inhibition. Besides these results, the intensity of enzymatic inhibition by cajá-umbu makes it a promising fruit for antidiabetic use [12].
In summary, cajá-umbu is a promising source of antioxidant activity, which could be relevant to treat diabetes, for instance. With this in mind, the cajá-umbu fruit is a promising alternative for conventional therapies, and holds valuable information that should promote other experimental studies. inhibition. Besides these results, the intensity of enzymatic inhibition by cajá-umbu makes it a promising fruit for antidiabetic use [12]. In summary, cajá-umbu is a promising source of antioxidant activity, which could be relevant to treat diabetes, for instance. With this in mind, the cajá-umbu fruit is a promising alternative for conventional therapies, and holds valuable information that should promote other experimental studies.

Conclusions
The Spondias genus has long been used in traditional medicine for various ailments. Different parts of this plant have been used in treatments, such as leaves, bark, fruits, branches, and roots. In this genus, there are different classes of bioactive compounds, including phenolics, flavonoids, carotenoids, quercetin, ellagic acid, and chlorogenic acid, among others, which are responsible for its biological activities. Among these activities, the ones that stand out are antioxidant, anti-inflammatory, anti-ulcer, antihyperlipidemic,

Conclusions
The Spondias genus has long been used in traditional medicine for various ailments. Different parts of this plant have been used in treatments, such as leaves, bark, fruits, branches, and roots. In this genus, there are different classes of bioactive compounds, including phenolics, flavonoids, carotenoids, quercetin, ellagic acid, and chlorogenic acid, among others, which are responsible for its biological activities. Among these activities, the ones that stand out are antioxidant, anti-inflammatory, anti-ulcer, antihyperlipidemic, hepatoprotective, thrombolytic, antimicrobial, antidiabetic, and anticancer. S. mombin L. has high antioxidant activity, it is used to treat neurological disorders in traditional African medicine, and in recent years it has begun to be further studied. S. dulcis is one of the most studied species among the Spondias sp. and its research is in regard to skin diseases, such as infections, and others illnesses, such as Alzheimer's, cancer, and diabetes. Studies with S. purpurea are rare, although it has been used for centuries in popular knowledge for diseases such as diabetes, diarrhea, and gastritis. S. tuberosa and S. pinnata are two of the least studied species, but show promising gastroprotective, antifungal, antibacterial, and antioxidant properties, among others. The most common activity reported in the literature for S. mombin × S. tuberosa is antioxidant, and it is a viable replacement for commonly utilized treatments. However, in regard to the limitations of this study, articles addressing the use of residues of this genus are lacking in the literature, especially for S. tuberosa and S. pinnata. As well as this, there are not many products on the market nor articles in the literature that actually use this genus as a final product. Therefore, the development of tests with other types of by-products of this genus and the production of pharmaceutical and cosmetic products are future perspectives of advances with the Spondias genus.

Data Availability Statement:
No new data were created or analyzed in this study. Data sharing is not applicable to this article.